Medicinal chemistry of the A3 adenosine receptor: agonists, antagonists, and receptor engineering

Abstract

A(3) adenosine receptor (A(3)AR) ligands have been modified to optimize their interaction with the A(3)AR. Most of these modifications have been made to the N(6) and C2 positions of adenine as well as the ribose moiety, and using a combination of these substitutions leads to the most efficacious, selective, and potent ligands. A(3)AR agonists such as IB-MECA and Cl-IB-MECA are now advancing into Phase II clinical trials for treatments targeting diseases such as cancer, arthritis, and psoriasis. Also, a wide number of compounds exerting high potency and selectivity in antagonizing the human (h)A(3)AR have been discovered. These molecules are generally characterized by a notable structural diversity, taking into account that aromatic nitrogen-containing monocyclic (thiazoles and thiadiazoles), bicyclic (isoquinoline, quinozalines, (aza)adenines), tricyclic systems (pyrazoloquinolines, triazoloquinoxalines, pyrazolotriazolopyrimidines, triazolopurines, tricyclic xanthines) and nucleoside derivatives have been identified as potent and selective A(3)AR antagonists. Probably due to the "enigmatic" physiological role of A(3)AR, whose activation may produce opposite effects (for example, concerning tissue protection in inflammatory and cancer cells) and may produce effects that are species dependent, only a few molecules have reached preclinical investigation. Indeed, the most advanced A(3)AR antagonists remain in preclinical testing. Among the antagonists described above, compound OT-7999 is expected to enter clinical trials for the treatment of glaucoma, while several thiazole derivatives are in development as antiallergic, antiasthmatic and/or antiinflammatory drugs.

Fig. 1

Structures of adenosine and widely used agonist probes of the A₃AR

Fig. 2

Structures of a novel, multiply substituted A₃AR agonists

Fig. 3

Structures of ribose ring-modified selective A₃AR agonist probes

Fig. 4

Structures of heterocyclic derivatives that are widely used as selective human A₃AR antagonists

Fig. 5

Thiazole and thiadiazole derivatives as human A₃AR antagonists

Fig. 6

Pyrazoloquinoline derivatives as human A₃AR antagonists

Fig. 7

Triazoloquinoxaline derivatives as A₃AR antagonists

Fig. 8

A₃AR antagonists based on a pyrazolo-triazolo-pyrimidine scaffold

Fig. 9

A₃AR antagonists based on quinoxaline and triazolobenzotriazinone scaffolds

Fig. 10

A₃AR antagonists based on nonnucleoside adenine scaffolds

Fig. 11

A₃AR antagonists based on triazolopurine scaffolds

Fig. 12

A₃AR antagonists based on tricyclic xanthine scaffolds

Fig. 13

A₃AR antagonists based on nucleoside scaffolds

Fig. 14

Compounds that interact selectively with the H272E mutant hA₃AR neoceptor